CN101641084B - 药物组合物 - Google Patents
药物组合物 Download PDFInfo
- Publication number
- CN101641084B CN101641084B CN2008800075975A CN200880007597A CN101641084B CN 101641084 B CN101641084 B CN 101641084B CN 2008800075975 A CN2008800075975 A CN 2008800075975A CN 200880007597 A CN200880007597 A CN 200880007597A CN 101641084 B CN101641084 B CN 101641084B
- Authority
- CN
- China
- Prior art keywords
- telmisartan
- sorbitol
- tablet
- lamella
- agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000008194 pharmaceutical composition Substances 0.000 title description 7
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- 239000005537 C09CA07 - Telmisartan Substances 0.000 claims abstract description 64
- 229960005187 telmisartan Drugs 0.000 claims abstract description 64
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims abstract description 46
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Classifications
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Abstract
本发明涉及药物片剂或片层，其包含呈无定形形式的血管紧张素II受体拮抗剂替米沙坦、碱性试剂和山梨糖醇，其特征在于该山梨糖醇具有0.75-3.5m2/g的比表面积。
Description
本发明涉及药物片剂或片层，其包含活性成份替米沙坦、碱性试剂和山梨糖醇。
替米沙坦(Telmisartan)为用于治疗高血压与其他医学适应症而开发的一种血管紧张素II受体拮抗剂，如EP-A-502314所公开。其化学名称为4′-[2-正丙基-4-甲基-6-(1-甲基苯并咪唑-2-基)-苯并咪唑-1-基甲基]-联苯-2-羧酸，其具有以下的结构：
替米沙坦以游离酸的形式制备和供应。其特征为在pH值介于1至7之间的胃肠道的生理pH范围内于水性系统中的溶解度非常差。如WO 00/43370中所公开，结晶替米沙坦存在两种具有不同熔点的多晶型。在热和湿度的影响下，较低熔点的多晶型B不可逆转地转化为较高熔点的多晶型A。此外，替米沙坦可以以无定形形式制备，亦即以一种固态溶液或具有＞50℃或优选＞80℃的玻璃化转变温度Tg的玻璃态制备。
替米沙坦可以剂量20mg、40mg及80mg的片剂形式购得。20mg的片剂为圆形的，其直径为7mm且高度为约2.5mm。40mg及80mg的片剂为椭圆形，含有氢氯噻嗪(HCTZ)作为第二活性成份的市售双层片剂也为椭圆形。椭圆形产品的长度介于12mm与16.2mm之间，宽度在5.8mm至7.9mm的范围内，且厚度为3.8mm至6.2mm。
替米沙坦的药理学功效需要在片剂中使用稀释剂。除了用于吞服的立即释放制剂外，还需要以类似于“欧洲药典(European Pharmacopeia)”的专论‘口服用片剂(Tablets for Use in the Mouth)’中的描述，配制含有替米沙坦的片剂或片层。如WO 03/059327中所公开，这意味着溶出特性是由侵蚀过程而非基质的崩解决定的，并且需要适宜的水溶性稀释剂。WO 03/059327公开了山梨糖醇作为用于替米沙坦的优选稀释剂，且注册的替米沙坦药物组合物包含山梨糖醇作为填充剂。此外，与替代性填充剂如木糖醇相比，山梨糖醇通常为较廉价的赋形剂。
另外，替米沙坦的不良溶解度和亲脂特性需要特殊手段以达到替米沙坦分别从片剂或片层规定的溶出速率。根据USP专论的定义，Q必须大于75％，优选大于85％。因此，根据本发明，必须确保30分钟之后，至少75％且通常至少85％的替米沙坦药物负荷溶解。
根据WO 03/059327，此类手段为在片剂中加入碱性试剂(此举有助于替米沙坦在水性介质中的溶出)，以及使用无定形替米沙坦(其可通过喷雾干燥获得)。
将D(0.5)定义一种粒径，其中50体积％的所用物质颗粒的粒径低于相应数值D(0.5)值，用以制备注册的替米沙坦药物组合物的无定形替米沙坦的粒径D(0.5)在20-55μm的范围内，而山梨糖醇的粒径D(0.5)在160-190μm的范围内，亦即超过150μm。较小粒径的山梨糖醇会提高稳定性以抵抗填充剂山梨糖醇、活性剂替米沙坦和药物组合物的其它组份的分开(demixing)，并且会使药物组合物具有改良且更易于重现的均一性。然而，粒径低于150μm的山梨糖醇无法产生所需硬度的片剂，实施例1的80mg替米沙坦片剂的硬度必须大于100N，优选大于130N，该硬度用Erweka TBH30仪器作为抗压强度(crushing strength)测定。对于圆形、扁平片剂(如实施例2的片剂)，如Newton等人(J.Pharm.Pharmac.23增刊，195S-201S(1971))所述表示为拉伸强度(tensile strength)，其为至少1.6N/mm2，优选＞2.1N/mm2。
药剂师知道，如果一方面活性成份与另一方面稀释剂的粒径相差大于2倍时，通常观察到各组份分开的技术问题，其对于含替米沙坦和山梨糖醇的注册的组合物也是如此(典型地175μm(山梨糖醇)：38μm(替米沙坦)＝4.6)。此尺寸的巨大差异最终导致了因其不符合注册的技术规格而不得不弃用该组合物。
在药物制备中，通常经由适当调节压实压力(compaction pressure)而获得片剂的指定硬度。对于加工允许达到最大的应力，该步骤可补偿批与批之间的压实性差异，后者归因于各成份的物理参数的自然差异。举例而言，根据WO 03/059327中所公开的方法制备的喷雾干燥的无定形替米沙坦可具有介于0.4与0.6g/ml之间的堆密度(bulk density)。
此外，已知压缩至较高硬度等级可导致溶出的削弱。因此，先前不可能始终获得显示溶出速率与硬度等级均在最优选等级的含替米沙坦的片剂或片层。
申请人现惊奇地发现，并不是用于制备含替米沙坦的片剂或片层的山梨糖醇的粒径而是比表面积主要决定片剂或片层的硬度以及活性成份替米沙坦的溶出速率(dissolution rate)。因此，本发明教导使用具有0.75-3.5m2/g的比表面积的山梨糖醇用于制备替米沙坦片剂或片层，而先前所用的山梨糖醇具有的比表面积为0.3-0.7m2/g。
比表面积如下测定：参考USP专论<846>，方法2，使用适宜的经校准BET仪器(Micromeritics ASAP 2400或等价物)，在77°K下及氮气中，。样品重量为3g至5g。将样品在40℃下在真空中除气2小时。在p/p0＝0.07-0.22下进行6点测定。
在＜60％的最大加工强度的压实压力的优选范围内，本发明所制备的片剂显示出改良的硬度以及较高的溶出速率，此外，溶出和硬度参数的重现性得到了显著地改善，从而使得同批内的差异及批间的差异均比较低。这最小化了注册规格不一致性的风险。
本发明中所述的药物组合物也可在组合替米沙坦和一或多种其它活性成份的固定剂量组合(例如在双层或三层片剂)中用作独立的片层。与含替米沙坦的层相组合的于独立层中的此类其它活性成份的实例为利尿剂，如氢氯噻嗪；钙受体拮抗剂，如氨氯地平；ACE抑制剂，如依那普利、赖诺普利、雷米普利等；HMG-CoA还原酶抑制剂，如辛伐他汀或阿托伐他汀；抗糖尿病药，如二甲双胍、格列酮(glitazones)和DPP-IV抑制剂。
因此，本发明的一个实施方案药物为片剂或片层，其包含例如于溶解片剂基质中的血管紧张素II受体拮抗剂替米沙坦、碱性试剂和作为稀释剂的山梨糖醇，其特征在于所述山梨糖醇具有0.75-3.5m2/g的比表面积。山梨糖醇的比表面积的优选范围为1.4-3.0m2/g，且最优选范围为2.0-2.5m2/g。
另外，用于本发明的制剂的山梨糖醇的特征为D(0.5)粒径为100-350μm，优选为120-300μm，且最优选为150-250μm。
为获得活性剂替米沙坦的所规定的溶出速率，优选使用粒径小于80μm，优选20-55μm的颗粒的无定形形式。此类无定形形式的替米沙坦可通过本领域的技术人员所熟知的任何适宜的方法制备，例如通过冷冻干燥水溶液、在流化床中涂覆载体颗粒，以及在糖丸粒或其它载体上的溶剂沉积而制备。然而，优选地，绝大多数的无定形替米沙坦通过WO 03/059327中描述的喷雾干燥方法制备，其中通过借助于一种或多种碱性试剂如氢氧化钠和/或葡甲胺，将替米沙坦溶解于纯水中而制备替米沙坦。任选地，可以添加增溶剂和/或重结晶阻滞剂。起始水溶液的干物质含量通常为10至50重量％，优选20至40重量％。然后将水溶液在室温下或优选在高温(例如50℃至100℃)下，在平流或对流喷雾干燥器中，在(例如)1至5巴的喷雾压力下喷雾干燥。通常而言，优选以一定方式选择喷雾干燥条件以便在旋风分离器(cyclone)中获得具有≤5重量％，优选≤3.5重量％的残留湿度的喷雾干燥颗粒。最终，喷雾干燥器的出口空气温度优选保持在约80℃至90℃，而相应地调节其它的加工参数，如喷雾压力、喷雾速度、入口空气温度等。所获得的喷雾干燥颗粒为优选具有以下粒径分布的细粒粉末：
d10：≤20μm，优选≤10μm
d50：≤80μm，优选20至55μm
d90：≤350μm，优选50至150μm。
在喷雾干燥之后，喷雾干燥颗粒中的活性成份替米沙坦以及赋形剂基本上处于无法检测到结晶度的无定形状态。在获得的替米沙坦颗粒中，可区分为低密度(0.4-0.5g/ml)与高密度(0.5-0.6g/ml)。
以100重量份的替米沙坦计，喷雾干燥颗粒优选含有5至200重量份的碱性试剂和任选的增溶剂和/或结晶阻滞剂。适宜的碱性试剂的具体实例为碱金属氢氧化物，如NaOH和KOH；碱性氨基酸，如精氨酸和赖氨酸；和葡甲胺(N-甲基-D-葡萄糖胺)，优选为NaOH和葡甲胺。
本发明的片剂一般含有10至160mg，优选20至80mg或40至80mg的替米沙坦。替米沙坦的优选剂量强度为20mg，40mg和80mg。
在另一个实施方案中，包含替米沙坦、山梨糖醇和碱性试剂的片剂或片层另外含有赋形剂和/或助剂，如粘合剂、载体、崩解剂、填充剂、润滑剂、流动控制剂、结晶阻滞剂，增溶剂、着色剂，pH调节剂、表面活性剂和乳化剂。优选选择用于片剂或片层组合物的赋形剂和/或助剂以便获得非酸性、速溶片剂基质。
本发明的片剂或片层一般包含3至50重量％，优选5至35重量％的替米沙坦；0.25至20重量％，优选0.40至15重量％的碱性试剂；和30至95重量％，优选60至80重量％的山梨糖醇。
混合分两个阶段进行，即在第一混合步骤中，使用如高剪切混合机或自由降落混合机(free-fall blender)，将喷雾干燥颗粒和稀释剂混合；且在第二混合步骤中，也优选在高剪切的条件下将润滑剂和预混合物混合。因此，通常将润滑剂如硬脂酸镁以占片剂或片层组合物重量的0.1至5重量％，优选0.3至2重量％的量加至预混合物中。然而，本发明的方法不限于这些混合方法，且通常可替代性的混合方法也应用各个加工步骤中。
其它的(任选)组份可以为，选自一种或多种下述含量的赋形剂和/或助剂：
10至30重量％，优选15至25重量％的粘合剂及载体；
0.01-5重量％的崩解剂；
0.01至5重量％，优选0.5至3重量％的润滑剂；
0.01至5重量％，优选0.3至2重量％的流动控制剂；
0.1至20重量％，优选2至8重量％的结晶阻滞剂；
0.01至10重量％，优选2至8重量％的增溶剂；
0.01至1.5重量％，优选0.1至0.8重量％的着色剂；
0.01至10重量％，优选2至8重量％的pH调节剂；
0.01至5重量％，优选0.05至1重量％的表面活性剂和乳化剂。
本发明的片剂略具吸湿性，且因此优选使用防潮性包装材料，如铝箔泡罩包装或聚丙烯管以及优选含有干燥剂的HDPE瓶来包装。
制备本发明的片剂或片层的优选方法包括：
a)制备替米沙坦、至少一种碱性试剂和任选的增溶剂和/或结晶阻滞剂的水溶液；
b)喷雾干燥该水溶液以获得喷雾干燥颗粒；
c)将该喷雾干燥颗粒与具有0.75-3.5m2/g的比表面积的山梨糖醇混合以获得预混合物；
d)将该预混合物与润滑剂混合以获得最终掺合物；
e)任选地，在步骤a)至d)中任一步中添加其它赋形剂和/或助剂；及
f)将该最终掺合物压制为片剂或片层。
所述方法可用于制备本发明的片剂或片层，该片剂或片层用于单独治疗高血压或组合治疗或预防选自下列的病症：慢性稳定型心绞痛(chronicstable angina)、血管痉挛性心绞痛(vasospastic angina)、中风、心肌梗塞、短暂性缺血发作(transient ischemic attack)、充血性心力衰竭、心血管疾病、糖尿病、胰岛素抵抗(insulin resistance)、葡萄糖耐受不良(impaired glucosetolerance)、糖尿病前期、2型糖尿病、糖尿病性肾病、代谢综合征(X综合征)、肥胖、血脂障碍(dyslipidemia)、高甘油三酯血症、C-反应蛋白的血清浓度升高、脂蛋白(a)的血清浓度升高、高半胱氨酸的血清浓度升高、低密度脂蛋白(LDL)-胆固醇的血清浓度升高、脂蛋白相关的磷脂酶(A2)的血清浓度升高、高密度脂蛋白(HDL)-胆固醇的血清浓度降低、HDL(2b)-胆固醇的血清浓度降低、脂连蛋白的血清浓度降低、认知衰退和痴呆。
尤其优选为额外治疗或预防慢性稳定型心绞痛、血管痉挛性心绞痛、中风、心肌梗塞、充血性心力衰竭、糖尿病、血脂障碍或痴呆。
最后，可使用适宜的压片机将本发明的片层与一层或多层包含其它活性成份的片层组合物压制至具有合适尺寸和抗压强度的目标片剂重量的多层片剂中，如双层片剂和三层片剂。为改善润滑，可在制备这些片剂期间使用用于冲模与冲压机的可选适宜的外部润滑剂喷雾系统。
为进一步示例性地说明本发明，给出以下非限制性实施例。
实施例
实施例1：包含80mg替米沙坦的片剂(层)
*挥发性组份，在最终产物中不残留
实施例2：包含40mg替米沙坦的片剂(层)
*挥发性组份，在最终产物中不残留
实施例3：包含20mg替米沙坦的片剂(层)
*挥发性组份，在最终产物中不残留
实施例4：80mg替米沙坦和12.5mg氢氯噻嗪(HCTZ)双层片剂
*挥发性组份，在最终产物中不残留
实施例5：80mg替米沙坦片剂(层)硬度的比较
片剂形状为椭圆形，16.2mm×7.9mm×4.6mm(长×宽×高)
a.使用具有0.5-0.7m2/g的比表面积的山梨糖醇
b.使用具有2m2/g的比表面积的山梨糖醇
*LD＝低密度 0.4-0.5g/ml
**HD＝高密度 0.5-0.6g/ml
实施例6：80mg替米沙坦片剂(层)溶出速率的比较
a.使用具有0.5-0.7m2/g的比表面积的山梨糖醇
b.使用具有2m2/g的比表面积的山梨糖醇
实施例7：20mg替米沙坦片剂(层)硬度的比较
片剂形状为圆形，直径为7mm，厚度为2.5mm
a.使用具有0.5-0.7m2/g的比表面积的山梨糖醇
b.使用具有2m2/g的比表面积的山梨糖醇
实施例8：替米沙坦片层硬度的比较
(80mg替米沙坦加上12.5mg氢氯噻嗪双层片剂)
a.使用具有0.5-0.7m2/g的比表面积的山梨糖醇
b.使用具有2m2/g的比表面积的山梨糖醇
实施例9：替米沙坦溶出速率的比较
(80mg替米沙坦加上12.5mg氢氯噻嗪双层片剂)
a.使用具有0.5-0.7m2/g的比表面积的山梨糖醇
b.使用具有2m2/g的比表面积的山梨糖醇
实施例10：40mg替米沙坦片剂(层)硬度的比较
(片剂形状为椭圆形，12.0mm×5.8mm×3.8mm(长×宽×高))
a.使用具有0.5-0.7m2/g的比表面积的山梨糖醇
b.使用具有1.3m2/g的比表面积的山梨糖醇
c.使用具有1.8m2/g的比表面积的山梨糖醇
d.使用具有2m2/g的比表面积的山梨糖醇
实施例11：40mg替米沙坦片层硬度的比较
(40mg替米沙坦加上12.5mg氢氯噻嗪双层片剂；
片剂形状为椭圆形，14.0mm×6.8mm×5.2mm(长×宽×高))
a.使用具有0.5-0.7m2/g的比表面积的山梨糖醇
b.使用具有1.4m2/g的比表面积的山梨糖醇
c.使用具有2m2/g的比表面积的山梨糖醇
Claims (16)
1.一种制备药物片剂或片层的方法，其中所述药物片剂或片层包含3至50重量％的呈无定形形式的血管紧张素II受体拮抗剂替米沙坦、0.25至20重量％的碱性试剂和30至95重量％的山梨糖醇；包括：
a)制备替米沙坦和至少一种碱性试剂的水溶液；
b)喷雾干燥该水溶液以获得喷雾干燥颗粒；
c)将该喷雾干燥颗粒与具有0.75-3.5m2/g的比表面积的山梨糖醇混合以获得预混合物；
d)将该预混合物与润滑剂混合以获得最终掺合物；
e)将该最终掺合物压制为片剂或片层。
2.权利要求1的方法，其特征在于所述山梨糖醇的比表面积为1.4-3.0m2/g。
3.权利要求1的方法，其特征在于所述山梨糖醇的比表面积为2.0-2.5m2/g。
4.权利要求1的方法，其中包含D(0.5)平均粒径为100-350μm的山梨糖醇。
5.权利要求1的方法，其中包含D(0.5)平均粒径为120-300μm的山梨糖醇。
6.权利要求1的方法，其中包含D(0.5)平均粒径为150-200μm的山梨糖醇。
7.权利要求1的方法，其中所述碱性试剂选自碱金属氢氧化物、碱性氨基酸和葡甲胺。
8.权利要求1的方法，其中所述药物片剂或片层含有10-160mg替米沙坦。
9.权利要求1的方法，其中所述药物片剂或片层含有20-80mg替米沙坦。
10.权利要求1的方法，其中所述药物片剂或片层含有40-80mg替米沙坦。
11.权利要求1的方法，其中使用平均粒径＜80μm的无定形替米沙坦。
12.权利要求1的方法，其中使用平均粒径为20-55μm的无定形替米沙坦。
13.权利要求1的方法，其中另外地在步骤a)至d)中任一步中添加其它的赋形剂或助剂。
14.权利要求13的方法，其中所述其它的赋形剂和助剂选自粘合剂、载体、崩解剂、填充剂、润滑剂、流动控制剂、结晶阻滞剂、增溶剂、着色剂、pH调节剂、表面活性剂和乳化剂。
15.权利要求13的方法，其中在步骤a)中制备的水溶液另外包含增溶剂和/或结晶阻滞剂。
16.权利要求1的方法在制备用于单独治疗高血压或组合治疗或预防选自慢性稳定型心绞痛、血管痉挛性心绞痛、中风、心肌梗塞、充血性心力衰竭、糖尿病、血脂障碍或痴呆的病症的片剂或片层中的用途。
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| Application Number | Priority Date | Filing Date | Title |
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| EP07104157A EP1970053A1 (en) | 2007-03-14 | 2007-03-14 | Pharmaceutical composition |
| EP07104157.8 | 2007-03-14 | ||
| PCT/EP2008/053009 WO2008110599A1 (en) | 2007-03-14 | 2008-03-13 | Pharmaceutical composition |
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| Publication Number | Publication Date |
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| CN101641084A CN101641084A (zh) | 2010-02-03 |
| CN101641084B true CN101641084B (zh) | 2013-04-10 |
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| EP (2) | EP1970053A1 (zh) |
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| KR (1) | KR101503674B1 (zh) |
| CN (1) | CN101641084B (zh) |
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| SI (1) | SI2120884T1 (zh) |
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| UY (1) | UY30961A1 (zh) |
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Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1908469A1 (en) | 2006-10-06 | 2008-04-09 | Boehringer Ingelheim Vetmedica Gmbh | Angiotensin II receptor antagonist for the treatment of systemic diseases in cats |
| US20100247649A1 (en) * | 2007-10-30 | 2010-09-30 | Dr. Reddy's Laboratories Ltd. | Pharmaceutical formulations comprising telmisartan and hydrochlorothiazide |
| WO2009135646A2 (en) | 2008-05-05 | 2009-11-12 | Farmaprojects, Sa | Stable pharmaceutical compositions and their processes for preparation suitable for industrial scale |
| CZ2008469A3 (cs) * | 2008-07-31 | 2009-10-29 | Zentiva, A. S. | Telmisartan tablety |
| GB0822171D0 (en) * | 2008-12-04 | 2009-01-14 | Arrow Int Ltd | Temisartan formulations |
| MX346039B (es) | 2009-05-20 | 2017-03-03 | Boehringer Ingelheim Vetmedica Gmbh | Solucion farmaceutica bebible de telmisartan. |
| WO2013142314A1 (en) * | 2012-03-19 | 2013-09-26 | Althera Life Sciences, Llc | Oral tablet formulation consisting of immediate release rosuv astatin and extended release metformin |
| JP6344678B2 (ja) * | 2013-09-27 | 2018-06-20 | キョーリンリメディオ株式会社 | テルミサルタン含有製剤及びその製造方法 |
| WO2015119289A1 (ja) * | 2014-02-10 | 2015-08-13 | 富士フイルム株式会社 | 口腔内崩壊錠 |
| BE1021954B1 (nl) * | 2014-06-05 | 2016-01-28 | Syral Belgium Nv | Samenstelling van sorbitol met lage friabiliteit |
| FR3023128B1 (fr) | 2014-07-01 | 2017-11-10 | Roquette Freres | Nouvelle composition edulcorante |
| JP5871294B1 (ja) * | 2015-02-27 | 2016-03-01 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 即時放出経口錠剤 |
| KR20170001921A (ko) | 2015-06-26 | 2017-01-05 | 대원제약주식회사 | 안정성이 개선된 텔미사르탄을 함유하는 약제학적 조성물 및 이의 제조방법 |
| CN106420739A (zh) * | 2016-10-31 | 2017-02-22 | 扬子江药业集团四川海蓉药业有限公司 | 一种替米沙坦氨氯地平双层片及其制备方法 |
| CN106800537B (zh) | 2017-01-18 | 2019-02-01 | 广东隆赋药业股份有限公司 | 丁苯酞-替米沙坦杂合物及其制备方法和用途 |
| CN109316451B (zh) * | 2017-07-31 | 2022-07-01 | 武汉朗来科技发展有限公司 | 治疗高血压和相关疾病的口服固体制剂 |
| SG11202010792TA (en) | 2018-05-02 | 2020-11-27 | Ferring Bv | Improved pharmaceutical formulations |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3245170A1 (de) * | 1982-12-07 | 1984-06-07 | Merck Patent Gmbh, 6100 Darmstadt | Verbesserter sorbit, verfahren zur herstellung und verwendung |
| AU1042199A (en) * | 1998-11-06 | 2000-05-29 | Boehringer Ingelheim International Gmbh | Antihypertensive medicaments containing lacidipine and telmisartan |
| FR2787110B1 (fr) * | 1998-12-11 | 2001-02-16 | Roquette Freres | Sorbitol pulverulent et son procede de preparation |
| PT1467712E (pt) * | 2002-01-16 | 2008-01-09 | Boehringer Ingelheim Pharma | Comprimido farmacêutico de duas camadas compreendendo telmisartan e hidroclorotiazida |
| DE10244681A1 (de) * | 2002-09-24 | 2004-04-08 | Boehringer Ingelheim International Gmbh | Neue feste Telmisartan enthaltende pharmazeutische Formulierungen und deren Herstellung |
| DE102004008804A1 (de) * | 2004-02-20 | 2005-09-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Mehrschichttablette |
| US20060078615A1 (en) * | 2004-10-12 | 2006-04-13 | Boehringer Ingelheim International Gmbh | Bilayer tablet of telmisartan and simvastatin |
| SI1814527T1 (sl) * | 2004-11-05 | 2014-03-31 | Boehringer Ingelheim International Gmbh | Dvoslojna tableta, ki obsega telmisartan in amlodipin |
| AU2005315855A1 (en) * | 2004-12-17 | 2006-06-22 | Boehringer Ingelheim International Gmbh | Combination therapy comprising telmisartan and hydrochlorothiazide |
| US20060159747A1 (en) * | 2004-12-17 | 2006-07-20 | Boehringer Ingelheim International Gmbh | Telmisartan and hydrochlorothiazide combination therapy |
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